Esomeprazole is the International Non-Proprietary Name (INN) of the chemical compound 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole. The CAS number for esomeprazole is 119141-88-7 and the CAS number for its sodium salt is 161796-78-7. The chemical structure of the esomeprazole sodium is included below:

Esomeprazole and its alkaline salts are proton pump inhibitors developed by AstraZeneca. They are effective inhibitors of gastric acid secretion and, therefore, are useful for the prevention and treatment of gastric acid-related disorders and inflammatory gastrointestinal diseases (e.g., gastric ulcer, duodenal ulcer, reflux esophagitis and gastritis).
Various methods of preparing esomeprazole are described in the art. Among these methods, are the ones which involve resolving racemic omeprazole using an optical resolution agent and, preferred in terms of commercial applicability, are the methods which involve asymmetrically oxidizing a precursor of esomeprazole using a chiral reagent.
The main problem with the oxidation reaction to convert the sulfide intermediate into the sulfoxide compound is over-oxidation, i.e. oxidation from sulfoxide to sulfone. The process of enantioselective oxidation, on increasing reaction scale, invariably leads to the formation of variable quantity of the sulfone impurity (cf. e.g. WO 2003/089408). The removal of sulfone impurity has often proved to be difficult with conventional purification methods such as crystallization, thus, time-consuming and costly processes must be carried out in order to obtain esomeprazole or its salts with high quality and quantity.
WO 1994/27988 describes the specific Na+, Mg2+, Li+, K+, Ca2+, and N(R)4+ salts of the two omeprazole enantiomers. In Example 1, esomeprazole sodium is prepared by reacting esomeprazole with sodium hydroxide using a mixture of methyl ethyl ketone and toluene from which the esomeprazole sodium precipitates. The subject matter related to esomeprazole sodium has been prosecuted in a divisional application of the corresponding European application EP 652872, which was published as EP 1020460.
In Example 11 of WO 1996/025235 esomeprazole sodium is prepared by reacting esomeprazole with sodium hydroxide in a mixture of methyl isobutyl ketone (MIK)/acetonitrile from which the esomeprazole sodium crystallizes.
In Example 41 of WO 2007/012650 esomeprazole sodium with deutered methoxy groups is prepared by reacting esomeprazole with sodium hydroxide in a mixture of methyl isobutyl ketone/isopropanol from which the esomeprazole sodium precipitates.
In Examples 1.1 to 1.3 of the International patent application WO 2006/001753 different solid forms of esomeprazole sodium are prepared by reacting esomeprazole with sodium hydroxide in a mixture of toluene/methanol, toluene/ethanol and toluene/isopropanol respectively.
Example 15 of WO 2008/149204 describes the preparation of esomeprazole sodium by dissolving esomeprazole in aqueous sodium hydroxide, extracting with methylene chloride, distilling-off the solvent, followed by addition of ethanol and distillation, addition of ethyl acetate and distillation, and final crystallization from ethyl acetate. Example 16 describes the preparation of esomeprazole sodium using sodium ethoxide as base and ethyl acetate as solvent.
Finally, Example 1-III of WO 2009/040825 describes the preparation of esomeprazole sodium by reacting esomeprazole with sodium hydroxide in methanol.
The preparation of the esomeprazole sodium in the conditions described in the previous documents show a low purification of esomeprazole sodium regarding the sulfone impurity with the exception of the process described in WO 2009/040825. However, it has been verified that the process described in this document yields to a methanol solvate. This fact shows the drawback that an additional step of converting the methanol solvate into the desolvated compound is needed. In addition, when desolvating the methanol solvate, the crystalline structure is lost and the esomeprazole sodium obtained is in amorphous form.
Thus, although there are known in the art several methods to prepare esomeprazole sodium which include crystallization or precipitation of the esomeprazole sodium from the reaction media, not good enough purification results are obtained regarding the sulfone impurity by crystallization/precipitation, a common technique used to purify organic compounds.
Other documents describe the preparation of esomeprazole sodium and isolation of the product by solvent evaporation, addition of a different solvent to the residue to isolate the esomeprazole sodium and filtering the product from the resulting suspension. However, these methods involving distilling-off completely the reaction solvent are not appropriate for industrial scale manufacture since they imply working with small volumes after solvent evaporation being often difficult to stir. They also involve problems of over-heating, problems of crude degradation, and problems related to the difficulty of removing the remaining solvent. In addition, it is necessary to carry out additional steps in order to isolate the final product. Among the documents where this type of isolation conditions are described are the following ones:
WO 2003/089408 describes the preparation of esomeprazole sodium by reaction of esomeprazole and aqueous sodium hydroxide or a sodium methoxide solution 30% w/v in methyl isobutyl ketone as solvent, distilling-off completely the solvent and then treating the obtained residue having the sulfone impurity with a solvent system comprising an organic solvent selected from ketone and nitrile in order to purify the sulfone impurity. According to the Examples, this purification is achieved by suspending the esomeprazole sodium first in acetonitrile and then in acetone.
WO 2004/052882 describes the preparation of esomeprazole sodium in water as solvent, followed by distilling-off the water and treating with acetonitrile.
WO 2004/002982 describes the reaction of esomeprazole and sodium hydroxide in methanol, distilling-off completely the solvent and then treating the solid obtained with diisopropyl ether.
WO 2007/013743 describes the treatment of a residue of esomeprazole sodium with a mixture of methyl isobutyl ketone and acetonitrile.
Finally, US 20070259921 describes several crystalline forms of esomeprazole sodium and processes for their preparation, some of them comprising the uses of ketones, alcohols and other solvents, and sodium bases. All the Examples describe processes involving distilling-off the reaction solvent before addition of another solvent.
Therefore, from what is known in the art it is derived that the provision of a purification process of esomeprazole sodium which remove the sulfone impurity and which proceeds with high yield, is still of great interest for the industrial manufacture of this compound.